Therapeutic Targeting of DGKA-Mediated Macropinocytosis Leads to Phospholipid Reprogramming in Tuberous Sclerosis Complex
- 16 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (8), 2086-2100
- https://doi.org/10.1158/0008-5472.can-20-2218
Abstract
Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease affecting primarily women and is the primary lung manifestation of tuberous sclerosis complex (TSC). In LAM, biallelic loss of TSC1/2 leads to hyperactivation of mTORC1 and inhibition of autophagy. To determine how the metabolic vulnerabilities of TSC2-deficient cells can be targeted, we performed a high throughput screen utilizing the "Repurposing" library at the Broad Institute, with or without the autophagy inhibitor chloroquine. Ritanserin, an inhibitor of diacylglycerol kinase alpha (DGKA), was identified as a selective inhibitor of proliferation of Tsc2-/- MEFs, with no impact on Tsc2+/+ MEFs. DGKA is a lipid kinase that metabolizes diacylglycerol (DAG) to phosphatidic acid (PA), a key component of plasma membranes. PA levels were increased 5-fold in Tsc2-/- MEFs compared to Tsc2+/+ MEFs, and treatment of Tsc2-/- MEFs with ritanserin led to depletion of PA as well as rewiring of phospholipid metabolism. Macropinocytosis is known to be upregulated in TSC2-deficient cells. Ritanserin decreased macropinocytic uptake of albumin, limited the number of lysosomes, and reduced lysosomal activity in Tsc2-/- MEFs. In a mouse model of TSC, ritanserin treatment decreased cyst frequency and volume, and in a mouse model of LAM, genetic downregulation of DGKA prevented alveolar destruction and airspace enlargement. Collectively, these data indicate that DGKA supports macropinocytosis in TSC2-deficient cells to maintain phospholipid homeostasis and promote proliferation. Targeting macropinocytosis with ritanserin may represent a novel therapeutic approach for the treatment of TSC and LAM.Other Versions
Funding Information
- NIH NIDDK (5R01DK102146-05)
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